Minutes

ITEM 1: APOLOGIES FOR ABSENCE/ANNOUNCEMENTS

2. Apologies for absence were received from the COC members Dr R Roberts and Professor D Shuker and the assessors Dr H Stemplewski (MHRA) and Mr A Browning (VMD).

Announcements

3. The Chairman welcomed D T England and Mr K Okona-Mensah (DH Toxicology unit at Imperial College London) and Dr D Gott attending for FSA.

4. The Chairman informed the Committee that he would not be able to attend the November COC meeting and that Professor Phillips had agreed to chair this meeting.

5. Members were reminded of the need to make any relevant declaration of interests before the discussion of items.

ITEM 2: MINUTES OF THE MEETING OF 26 JUNE 2003

6. The minutes were agreed subject to minor editorial changes.

ITEM 3: MATTERS ARISING NOT COVERED BY LATER AGENDA ITEMS

7. Members were informed that the COC statement on carcinogenic impurities present in the pesticide 1-methylcyclopropene had been agreed. The COC advice had been sent to the Advisory Committee on Pesticides (ACP) and was included in a submission to DEFRA ministers. Subsequently, ministers agreed to grant an approval for the 1-methylcyclopropene pesticide product.

8. The Committee heard that a final draft of the COC guidelines for chemical carcinogen risk assessment had been produced, and circulated to members for comment by 28th September 2003. The document would then be made available for wider consultation. It was proposed that any comments would be reviewed at the COC March 2004 meeting.

9. Members were also informed that the COC statement on environmental tobacco smoke had been agreed by Chairman's action and had now been placed on the COC website.

10. Regarding horizon scanning, one member raised the interpretation of 'as low as reasonably practical' (ALARP in the context of genotoxic carcinogens). Members noted this suggestion, but felt that this was a risk management issue and would be taken up by regulatory authorities and government departments as appropriate.

11. One member also asked that the Committee should give some future consideration to the dose-response relationship for genotoxic carcinogens at low doses and the effect of DNA repair processes.

ITEM 4: ALCOHOL AND BREAST CANCER (AMMENDED CC/03/24)

12. The minutes of this item now published - see paragraphs 54 - 64.

ITEM 5: PRESENTATION ON BIOBANK PROJECT (CC/03/25 AND ADDENDUM)

13. The Chairman welcomed Dr Peter Greenaway (Assistant Director of Research and Development Division, Department of Health) to the meeting. Dr Greenaway provided COC members with copies of his overheads. (A brief summary of the presentation is given in the minutes).

14. Dr Greenaway noted that the publication of the draft code for the human genome and new techniques for rapid sequencing Single Nucleotide Polymorphisms of DNA had opened the way for research to investigate the combined effects of genetics and lifestyle or environmental factors on common multifactorial diseases of adult life. Dr Greenaway considered that the strong scientific base in the UK, the population size and diversity and the almost universal coverage of the NHS indicated that large scale prospective research on disease occurrence and genetics was feasible in the UK. A key factor in the design of the study would be including enough individuals so that sufficient clinical outcomes could accrue within a reasonable period of time. For this reason, the Biobank would be established with a minimum of 500,000 individuals aged between 45-69y with a follow-up period of 10 years. People registered with general practices would be asked to join the study. Participants would be asked to complete a self-administered questionnaire and interview with a research nurse, give a blood sample, and sign a consent form for participation and follow-up. Participating individuals would be flagged through the ONS and incident data on morbidity would be obtained through practice records and hospitalisation data. Dr Greenaway commented that the policy for participation was "opt-in", and that individuals would be able to leave the project at any time. He noted that it was expected that new clinical diagnoses would be identified for approximately 10% of individuals at entry to the project. Such information would be fed back to individuals via their GPs. However Biobank wouldn't undertake to be responsible for passing information on subsequent diagnoses (eg following hospitalisation) to participating individuals.

15. The Biobank project was jointly funded by the MRC (£28 M), the Wellcome Trust (£28 M) and the Department of Health (£6M). A web site had been established which provided information on the planning of the project. (http://www.ukbiobank.ac.uk/). The co-ordinating Centre for the project is based at Manchester Science Park, and it is hosted by the University of Manchester. A not-for-profit company limited by guarantee will be established to run the venture (HUBCO). The Biobank project was envisaged as providing a resource for researchers to undertake nested-case control studies to evaluate hypotheses. A key feature of the Bobank project was public ownership of the data accumulating from such investigations.

16. Dr Greenaway gave a brief overview of the structure of the Biobank management team. A Board of Directors, accountable to the Members of the Company (the Medical Research Council and The Wellcome Trust), would act as company directors under UK company law and as charity trustees under UK charity law and exercise management oversight of UK Biobank Limited. They will have overall responsibility for the direction, management and control of UK Biobank Ltd. The Board is chaired by Sir Alan Langlands, Principal and Vice Chancellor of the University of Dundee, and former Chief Executive of the National Health Service for England. A Science Committee, chaired by Professor John Bell from Oxford University, had been established. It will be a committee of the Board of Directors. Amongst other things it will be responsible for advising the Board on the direction and scientific objectives of UK Biobank and the development of the scientific protocol. Together with the Biobank CEO, the Science Committee will also advise on future activities of strategic importance, such as collaborations or further development of the protocol. An Ethics and Governance Council will be appointed to serve as an independent guardian of the Ethics and Governance Framework, and to advise the UK Biobank and report publicly on the conformance of its activities with the Framework and with the interests of participants and the public.

17. Members of the Scientific Committee and their responsibilities had been published on the Biobank internet site. Dr Greenaway particularly noted the important functions of recruitment (Professor Stephen Palmer, Cardiff) questionnaire design (Professor Valerie Beral, Oxford), data management (Professor Richard Durbin, Sanger Institute) and sample storage (Professor Paul Elliot, Imperial College London). He noted that, although the basic approach to these topics had been fully discussed by the Scientific Committee, there was still time before pilot projects were undertaken, to influence the approach taken. Thus methods for recruitment, the extent of follow-up and level of information collected at interview were open to suggestions from research colleagues. Members of the Biobank Scientific Committee were keen to ensure public support for the project and thus the nature and extent of questions asked, in particular the time required to undertake the questionnaire and the storage of samples and their subsequent use, needed to be carefully considered. At present the Scientific Committee envisaged that a detailed questionnaire covering information on chemical exposures (eg as a result of occupation) might be developed for a proportion of individuals. It had been estimated that the cost of the project would increase by approximately £0.5M, for every additional 2-3 minutes of time needed by the research nurse to evaluate the questionnaire.

18. Dr Greenaway concluded by noting that similar projects initiated in the USA had begun to yield some interesting research results. Hence the recent findings from the US Environmental Genome Project (http://www.niehs.nih.gov/envgenom/home.htm) that consumption of folate influenced the risk of leukaemia associated with exposure to benzene. Biobank represented the most important step towards similar research in the UK.

19. The Chairman thanked Dr Greenaway for his presentation and asked members for questions.

20. Members suggested that it would be valuable if there were ways of linking Biobank to other projects to expand the cohort size. Dr Greenaway noted that the Scientific Committee had considered this idea, but there were problems concerning conformity of data acquisition and information transfers and consent for information transfers suggested that collaboration to expand databases would prove difficult. He noted that there were proposals for similar projects in France, Germany, and Sweden. It was expected that the EU Commission would take a central role in attempting to co-ordinate information transfer between these projects. Members asked about the relationship between trustees and the approval of research proposals. Dr Greenaway noted that the Ethics and Governance Council essentially had powers to veto any research proposals, which did not conform to the highest levels of ethics. He confirmed that no information would be provided to insurance companies and any request for use of data or samples by the police would be subject to a legal challenge.

21. Members questioned the recruitment procedures and asked about how the cohort would be representative of the whole UK population. Members were concerned regarding under-representation by lower socio-economic groups, males and ethnic minorities and also by possible over-representation by "healthy" individuals. Dr Greenaway agreed that one challenge was to obtain sufficient numbers of volunteers from across the UK population. Members also noted that the quality assurance procedures for the handling and analysis of samples would be critical. Members asked if there would be any initial analyses of samples for quality assurance purposes. Dr Greenaway agreed that quality control of sample handling and analyses were critical. He noted that in view of the large number of samples to be analysed that accreditation of laboratories before they undertook analyses would be important. It would also be important to ensure the quality of laboratory analyses for any subsequent investigations undertaken by researches.

22. Members queried the extent of information that would be obtained for occupational history and in particular for chemical exposure. Members were concerned that a single administered questionnaire would provide only limited information on potential chemical exposures and on lifestyle factors (eg smoking, drinking alcoholic beverages). In addition without follow-up evaluation of exposures it was unlikely that any meaningful results could be derived from the Biobank project. Dr Greenaway noted these comments and noted that there was a proposal for more detailed follow-up of some individuals, but there were concerns from the Biobank Scientific Committee regarding ensuring participation, particularly if the questionnaire took a long time to complete. Members queried whether individual researchers would be allowed to contact cohort members for additional data, as part of their investigations. Dr Greenaway felt that access to cohort members would depend on the consents agreed at entry to the study. Dr Greenaway noted that the Biobank project team was aware of the potential problems which might limit researchers ability to gain retrospective information and to follow-up members of the cohort.

23. Members asked about the method used to ascertain disease end points. It was felt that there were good data on cancer, via registries, but some clinical diagnoses such as diabetes and pyschiatric conditions might be difficult to elucidate from information sources available to Biobank. Dr Greenaway considered that prescribing information might assist in some instances.

24. The Chairman thanked Dr Greenaway for attending the Committee. Dr Greenaway thanked members for the opportunity to present to COC and noted that it was unlikely that pilot studies would be initiated before 2005 and hence there was time to input ideas regarding the conduct of the Biobank project.

ITEM 6: CARCINOGENICITY OF POLYCYCLIC AROMATIC HYDROCARBONS (PAHs)

6.1 1st draft statement on dibenzo(a,l)pyrene (CC/03/27)

25. The Committee considered a review of published carcinogenicity data on dibenzo(a,l)pyrene (DB(a,l)P) at its November 2002 meeting. Members agreed that it was prudent to conclude that DB(a,l)P is between 10-100 times more potent than benzo(a)pyrene depending on the route of administration and animal test system used.

26. Members considered the draft statement in detail and requested that further information on DNA adducts should be inserted where available in the relevant sections. It was intended that the statement would be amended in light of members' comments and cleared by Chairman's action.

6.2 Approaches to risk assessment of PAHs in air pollution (CC/03/26)

27. A review had been drafted on existing approaches to carcinogenic risk assessment of PAHs in air pollution. This had been prompted by the recent monitoring data indicating the presence of the high potency PAH, DB(a,l)P, in some samples. Members were asked to comment on this draft review, which after amendment, would be submitted for publication to a peer review journal. The COM at its May 2003 meeting had considered an earlier draft.

28. Three approaches to PAH carcinogenic assessment have been advocated: the use of carcinogenic Potency Equivalency Factors (PEFs); the complete mixture method; and use of B(a)P as a surrogate carcinogen for all PAHs. The B(a)P surrogate approach is currently used to monitor for compliance with a UK air pollution standard. This approach may not be appropriate if PAHs with a higher carcinogenic potency relative to B(a)P are present in air pollution and the levels of these compounds vary significantly compared with those of B(a)P.

29. The review paper took account of available carcinogenicity data and included discussion of kinetics of PAH uptake via the lung and self-induction of PAH metabolism. The aim was to identify the most appropriate experimental approach to setting PEFs. It was acknowledged that it would not be possible to undertake inhalation carcinogenicity studies for all PAHs that would require carcinogenic potency ranking to assist in developing PEFs. Therefore the paper examined whether any surrogate endpoint could be developed. The COM agreed that DNA adducts could be used as a pragmatic surrogate for carcinogenic potency in this instance for the consideration of PAHs, for air pollution. The COM agreed that a single intratrachael instillation dose would be the most appropriate for this purpose.

30. Members noted that UK air monitoring data and graphs provided to the committee did not match, and asked for this discrepancy to be clarified. Members also asked whether air pollution levels of PAHs in the UK were similar to those in the USA. The Committee was informed that air monitoring of DB(a,l)P had only recently been initiated as part of the routine monitoring for PAHs and therefore it was not yet possible to make a good comparison between levels over time or geographically.

31. One member suggested that if levels of D(a,l)P were found to be no more than a hundredth of B(a)P levels, overall it would be approximately equal to B(a)P in terms of potency. The COC agreed it would be useful to have a future discussion on the B(a)P surrogate approach to carcinogen risk assessment at some point in the future. The committee agreed that was important to find out the proportion and variation of high potency PAHs in the UK, as detected by air monitoring.

32. The COC agreed that, in general, PAHs were activated by metabolism to proximate carcinogens via the diol-epoxide pathway. One exception, dibenz (a,h) anthracene was noted.

33. Members agreed with the suggested approach for ranking PAHs with respect to carcinogenic potency by inhalation exposure ie measurement of time integrated DNA adducts in lung tissue following single intratracheal administration to rats. These results could be used with data on air levels (derived from a range of sites in the UK at different time intervals) to evaluate variation in carcinogenic potency of PAHs in air pollution. The outcome of this research would help review whether a PEF or B(a)P surrogate approach to the air quality standard was most appropriate for the risk assessment of PAHs in air pollution.

34. One member noted that induction of PAH metabolism after repeated administration needed to be considered. In addition differential repair of DNA adducts formed from PAHs had to be considered. The Committee was aware that both the USA and the EU were conducting ongoing research projects on PAH carcinogen risk assessment, which would be useful for future consideration.

ITEM 7: ORGANOCHLORINE INSECTICIDES AND RISK OF BREAST CANCER (CC/03/4 re-issued)

35. In 1995, the COC reviewed the available epidemiological data on DDT and its isomers/metabolites, and the hexachlorocyclohexane isomers gamma-HCH (lindane) and beta-HCH. The Committee agreed that there was no clear association of breast cancer with these chemicals. However, it was felt that the matter should be kept under review. A further review led to a revised statement being agreed in 1999. The 1999 review included an additional compound, dieldrin, as new epidemiological data on this chemical had become available. All pesticide uses of organochlorine insecticides (OCls) included in these reviews have now been phased out.

36. Paper CC/03/4 provided an overview of the epidemiology on the above chemicals published since 1999. Details from a recent symposium held by Sir Richard Doll (on 21 November 2002) (CC/03/11) were also provided to members.

37. Short summaries of all the new studies were provided and full papers of the epidemiology studies with positive findings were appended. Of the nineteen studies reported, thirteen reported no significant effect of organochlorines on breast cancer risk. The Committee was informed that 4 out of the 6 epidemiology studies reporting a positive association between organochlorines and breast cancer came from a group based in Denmark. The Chairman of the COC had previously written to the Lancet with regard to the potential that the association between dieldrin and breast cancer reported by Hoyer and colleagues in 1998 might have been due to chance. The authors had undertaken multiple comparisons involving 46 chemicals, but had focused the published report on the positive associations found only for selected chemicals. A similar criticism might apply to the more recent studies. It was noted that all of these four studies were based on serum determinations of dieldrin and that the relevance of such data for prediction of long term exposure to dieldrin is questionable.

38. Members agreed that there was a lot of new data to consider. Members asked that the data be re-tabulated to show the results for each chemical entity rather than separated into positive and negative studies. It was noted that paper CC/03/11 contained a useful plot of odds ratios with 95% confidence intervals of the associations between breast cancer and DDE for a number of studies. This plot showed that the lower estimate of the 95% confidence intervals in most studies fell below zero, suggesting no association. But, the earliest study (Wolf et al 1993) reported the highest odds ratio 3.68 (95% CI 1.07-13.50), and this may have been responsible for generating further work. It was suggested that such a plot might be useful for the other organochlorine chemicals.

39. Members considered that studies by Woolocott et al (2001) and Romieu et al (2000) reporting positive associations between organochlorines and breast cancer were good studies. However the Romieu et al study which found a positive association between DDE in serum and an increased risk of breast cancer, was a relatively small study. The Woolocott study found a greater association between DDE in breast adipose tissue with oestrogen receptor negative breast cancer, and this appeared to be associated with a poorer prognosis.

40. The Committee felt that needed to see some of the negative studies in full, and asked for these to be provided at the next meeting. Members were informed that data on the oestrogenicity of these compounds and data on the trends of serum concentration over time, from UK monitoring studies, would be provided for consideration at the next meeting.

41. The COC was also informed that some of the papers identified in the symposium held by Sir Richard Doll (CC/03/11) and any further relevant identified papers would be presented at the November 2003 COC meeting.

ITEM 8: COM STATEMENT ON HIGH DOSE POSITIVE MUTAGENS (CC/03/29)

42. The Committee was asked whether it had any comment on the COM statement on high dose positive mutagens. This statement had been provided essentially for information.

43. The COM had given consideration as to whether any generic advice could be provided on the interpretation of in-vivo bone marrow mutagenicity data that may give rise to concern as being a false positive. For example, evidence of in-vivo mutagenicity from such tests where severe toxicity in the dosed animals could produce concern over the relevance of the data. Additionally, it was known that positive results could be obtained in the in-vivo bone marrow mouse micronucleus test by mechanisms that induce hypothermia, hyperthermia, and stimulation of erythropoiesis and possibly due to indirect severe cytotoxicity in the bone marrow. In such cases the positive results, if not supported by other in-vivo data, could be regarded as artefacts, which did not reflect mutagenicity of the compound itself in animals.

44. Two members of the COC had contributed to the COM consideration, because of the importance of adequate carcinogenicity bioassays in assessing such data. The guidance emphasised the importance of considering all the available relevant data when assessing whether a compound was an in-vivo mutagen.

45. The COC agreed that this was a very good and useful document and had no further comments. The Committee was informed that this paper would be placed on the COM web-site.

ITEM 9: HORIZON SCANNING (CC/03/30)

46. The COC was provided with information describing the setting up of a National Cancer Tissue Resource. The establishment of such a resource was identified in the 1996 COC discussion on research priorities and discussed in the Horizon scanning paper CC/03/22. Members were asked to provide any comments to the secretariat.

ITEM 10: PAPERS FOR INFORMATION

10.1 PAH Air monitoring data (in-confidnce unpublished data)

47. Data from AEAT Technology (AEAT have a contract to provide air monitoring data to DEFRA) had been provided for information (CC/03/31). This had been requested previously by the COM. One member noted discrepancies in the reporting of data as presented to the COC. It was agreed that no comments could be made with regard to these data until the secretariat had discussed the results with the authors.

ITEM 11: ANY OTHER BUSINESS (CC/03/32)

48. Paper CC/03/32 was tabled for information. The FSA representative informed the COC that the advice of the Chairmen of the COT, COC, and COM had been sought on the presence of SUDAN I in chilli powder.

49. In May 2003 the French Food authority had detected the azo dye Sudan I in a number of products containing chilli powder imported from India. Subsequently the FSA have found Sudan I in some food products containing chilli powder imported from India. Products affected included 'Tandoori Sauce', 'Mixed Pickle' and 'Flaming hot Chutney'. Levels of Sudan I detected in the UK had been similar to those in France in the range of 1000 ppm.

50. There is evidence that Sudan I is carcinogenic in rodents and mutagenic both in vitro and in vivo. Following FSA consultation with the Chairmen of the COT, COC, and COM, it was agreed that although there were some incomplete and possibly equivocal results, it was prudent to assume that Sudan I is a genotoxic carcinogen and that dietary exposures should be as low as reasonably practicable (ALARP).

51. Based on this advice and the fact that Sudan I is not a permitted food additive, the FSA had worked with Local Authorities and Industry to ensure that products containing Sudan I did not enter or were removed from the food chain. The Agency had also issued press releases informing consumers of the products contaminated with Sudan I, and advised people not to eat any of the affected products.

52. Legislative action had been taken by the EU to try and prevent any further contamination of food with Sudan I, and investigations were ongoing to determine whether any other products were affected.

ITEM 12: DATE OF NEXT MEETING

53. Date of next meeting 6 November 2003.

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ITEM 4: ALCOHOL AND BREAST CANCER (AMMENDED CC/03/24)

54. The Committee was told that members’ comments on the draft Imperial College systematic review made at the 26 June 2003 meeting had been passed to the authors. Further discussions regarding the presentation of the effect of drinking alcoholic beverages on the cumulative incidence of breast cancer had resulted in the submission of a revised graph. In addition a revised calculation of the Population Attributable Risk was also available. The draft “Lay Summary” had been extensively revised and simplified. Following consultation with members, the secretariat had proposed that this document be renamed “Summary Report”. The Committee was asked to comment on the 4th draft statement (amended for 22 September meeting) and the 2nd draft lay summary document.

55. Members made a number of drafting comments. (Editorial comments and minor suggested alterations have not been summarised in the minutes).

56. Regarding the introduction section, members asked that a single listing of the risk factors for breast cancer be given and commented that certain oral contraceptive and hormone replacement therapy should be considered as risk factors for breast cancer (not as “proposed” risk factors).

57. Members commented that there was still some confusion in both the full statement and lay summary regarding the results of the Imperial College systematic review which were reported in terms of drinks consumed per day (where each drink was assumed to contain approximately 9.5 g ethanol) and the information on intakes and cumulative incidence which reported trends of intake in terms of units of alcohol consumed (where each unit is equivalent to 8 g ethanol). Members asked that an appropriate conversion be undertaken to calculate risk in terms of units consumed per day be undertaken.

58. Members asked for a further sentence to be added to explain the reason why meta-regression had been undertaken. Members noted that studies included in the systematic review undertaken by Imperial College did not permit an assessment of the cumulative incidence of breast cancer in non-drinkers.

59. Members considered that the final sentence of the consideration of causality should read “Overall the Committee considered it was prudent to assume that a causal association exists.”

60. The Committee considered that in the section on significance to public health it was important to indicate that the estimates of additional breast cancer cases attributed to alcohol referred to increases in alcohol consumption over the average intakes for women in the UK. Members agreed it was relevant to specify the age range for the research on alcohol consumption in younger women in the statement, but it was more important that any conclusion referred to young women in general as increasing intakes were not restricted to 16-24 years of age. Members also considered that if alcohol consumption in younger women were maintained during their life-time then this would result in an increase in the number of breast cancer cases attributed to alcohol, not the risk associated with drinking as stated in the current draft of the statement. (Members agreed that these points were also relevant to the lay summary document see paragraph 57 below).

61. The Committee agreed that the order of the conclusions should be rearranged to report the results of the systematic review undertaken by Imperial College first. In this respect, members agreed that the conclusion should document increased risks associated with consumption of units of alcohol. Members agreed that the conclusion reporting the assessment of cumulative risks should be subdivided to clarify the message. The remaining conclusions should be listed in the following order; the interpretation of the Oxford collaborative study, the information on potential mechanisms by which drinking alcohol could cause breast cancer, the overall COC conclusion on causality, the conclusion on interaction between alcohol and oral contraceptive and HRT use, and finally the conclusion on the potential significance of increasing alcohol consumption in younger women for public health.

62. The Committee discussed the “lay summary” and agreed that this document should be entitled “non-technical summary”. Members agreed that the document had been shortened and technical detail omitted. However it was felt that the number of footnotes needed to be reduced. Regarding information on other potential risk factors for breast cancer, members considered that a reference to the information note produced by the Cancer Research UK (http://www.cancerresearchuk.org/aboutcancer/specificcancers/breastcancer) would be appropriate.

63. Members agreed the non-technical summary should only report intakes in terms of units of alcohol consumed. The Population Attributable Risk should be reported in terms of a range. The cumulative incidence of breast cancer and effect of drinking alcoholic beverages should be reported in terms of numbers/1,000 women. In addition the reference to an age range for younger women should be omitted.

64. Members were informed that the publication of the COC statement and non-technical summary would be coincident with the publication of the Imperial College systematic review. The revised documents would be circulated for members’ comments and agreed via Chairman’s action.

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ACTIONS

ITEM	ACTION	WHO
4. Alcohol & breast cancer	Finalise statement By postal consultation	Secretariat/ Chairman
6. Carcinogenicity of PAHs	Revise statement on DB(a,l)P. Revise paper on PAHs	Secretariat
7. Organochlorines & breast cancer	Provide tabulation/graphs. Additional paper on oestrogenicity of OCIs	DH Toxicology Unit/ Secretariat

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